tbuckley/cabot-search huggingface dataset:
Assessing Mental Illness Risk Among North Korean Refugees and Immigrants Resettled in South Korea
Authors: Rugyeom Lee, Sang Min Lee, Minha Hong, In-Hwan Oh
Journal: JAMA Network Open (2022)

Importance The global increase in the numbers of refugees and immigrants has made mental health a major public concern. Although they are divided, North and South Korea share a common ethnic heritage. Objective To investigate mental illness risk among North Korean immigrants living in South Korea and compare it with that of the general South Korean population. Design, Setting, and Participants This retrospective, population-based cohort study was based on National Health Insurance claims data from 2007 to 2019, and North Korean immigrants and refugees (NKIRs) and age-matched and sex-matched members of the general population (GP) were included with a 1:3 ratio. Data were analyzed from March 2022 to August 2022. Exposure Emigration from North Korea to South Korea. Main Outcomes and Measures Mental illness incidence and risk through a Cox proportional risk model adjusted for sex, age, disability, region, Charlson Comorbidity Index score, and insurance premium percentile. Results A total of 37 209 NKIRs and 111 627 members of the GP were enrolled. The final analysis examined 112 851 individuals (73 238 [64.9%] female, median [IQR] age 34 [19-47] years), with 90 235 (80.0%) in the GP and 22 616 (20.0%) in the NKIR group. The propensity score–matching population numbered 24 532 in total, with 12 266 each in the NKIR and GP groups. NKIR patients had a higher mental illness risk than the GP (hazard ratio [HR], 2.12; 95% CI, 2.04-2.21). The multivariable adjusted HRs (95% CI) for developing mental disorders were 4.91 (3.59-6.71) for posttraumatic stress disorder, 3.10 (2.90-3.30) for major depressive disorder, 2.27 (2.11-2.44) for anxiety and panic disorder, 2.03 (1.58-2.60) for bipolar affective disorder, 1.85 (1.53-2.24) for alcohol use disorder, and 1.89 (1.46-2.45) for schizophrenia. Conclusions and Relevance In this study, NKIR individuals showed a significantly higher risk of developing most mental disorders. Interventional strategies can prevent psychiatric morbidity and ensure adequate care for this population.
SF3B1 mutated MDS: Blast count, genetic co-abnormalities and their impact on classification and prognosis
Authors: Sandra Huber, Torsten Haferlach, Manja Meggendorfer, Stephan Hutter, Gregor Hoermann, Constance Baer, Wolfgang Kern, Claudia Haferlach
Journal: Leukemia (2022)

Recently, MDS with mutated SF3B1 and blast count <5% was proposed as distinct entity with favorable prognosis by the international working group for the prognosis of MDS (IWG-PM), the 5th edition of the WHO classification and the International Consensus Classification. To further characterize this entity with respect to the genomic landscape, AML transformation rate and clinical outcome, we analyzed 734 MDS patients by whole genome sequencing. SF3B1 mutations were identified in 31% (n = 231), most frequently accompanied by TET2 mutations (29%). 144/231 (62%) SF3B1
Population-Based Estimates of 1-Year Mortality After Major Surgery Among Community-Living Older US Adults
Authors: Thomas M. Gill, Brent Vander Wyk, Linda Leo-Summers, Terrence E. Murphy, Robert D. Becher
Journal: JAMA Surgery (2022)

Despite their importance to guiding public health decision-making and policies and to establishing programs aimed at improving surgical care, contemporary nationally representative mortality data for geriatric surgery are lacking.
Association of Intravenous Potassium and Magnesium Administration With Spontaneous Conversion of Atrial Fibrillation and Atrial Flutter in the Emergency Department
Authors: Filippo Cacioppo, Denise Reisenbauer, Harald Herkner, Julia Oppenauer, Nikola Schuetz, Jan Niederdoeckl, Sebastian Schnaubelt, Sophie Gupta, Martin Lutnik, Alexander Simon, Alexander O. Spiel, Nina Buchtele, Hans Domanovits, Anton N. Laggner, Michael Schwameis
Journal: JAMA Network Open (2022)

Whether the simultaneous intravenous administration of potassium and magnesium is associated with the probability of spontaneous conversion to sinus rhythm (SCV) in the acute treatment of atrial fibrillation (AF) and atrial flutter (AFL) is unknown.To assess potassium and magnesium administration and SCV probability in AF and AFL in the emergency department.A registry-based cohort study was conducted in the Department of Emergency Medicine of the Medical University of Vienna, Austria. All consecutive patients with AF or AFL were screened between February 6, 2009, and February 16, 2020.Intravenous administration of potassium, 24 mEq, and magnesium, 145.8 mg.The primary outcome was the probability of SCV during the patient's stay in the emergency department. Multivariable cluster-adjusted logistic regression was used to estimate the association between potassium and magnesium administration and the probability of SCV.A total of 2546 episodes of nonpermanent AF (median patient age, 68 [IQR, 58-75] years, 1411 [55.4%] men) and 573 episodes of nonpermanent AFL (median patient age, 68 [IQR, 58-75] years; 332 [57.9%] men) were observed. In AF episodes, intravenous potassium and magnesium administration vs no administration was associated with increased odds of SCV (19.2% vs 10.4%; odds ratio [OR], 1.98; 95% CI, 1.53-2.57). In AFL episodes, in contrast, no association was noted for the probability of SCV with potassium and magnesium vs no administration (13.0% vs 12.5%; OR, 1.05; 95% CI, 0.65-1.69).The findings of this registry-based cohort study on intravenous administration of potassium and magnesium suggest an increased probability of SCV in nonpermanent AF, but not AFL, during a patients' stay in the emergency department.
Evaluation of Prefrontal γ-Aminobutyric Acid and Glutamate Levels in Individuals With Major Depressive Disorder Using Proton Magnetic Resonance Spectroscopy
Authors: Christopher Ritter, Andreas Buchmann, Sabrina Theresia Müller, Martin Volleberg, Melanie Haynes, Carmen Ghisleni, Ralph Noeske, Ruth Tuura, Gregor Hasler
Journal: JAMA Psychiatry (2022)

Major depressive disorder (MDD) is one of the most prevalent illnesses worldwide. Perturbations of the major inhibitory and excitatory neurotransmitters, γ-aminobutyric acid (GABA) and glutamate (Glu), respectively, as well as Glx (Glu or glutamine [Gln]) have been extensively reported in a multitude of brain areas of individuals with depression, but few studies have examined changes in Gln, the metabolic counterpart of synaptic Glu.To investigate changes in GABA, Glx, Glu, and Gln levels in a voxel in the left dorsolateral prefrontal cortex of participants with no, past, and current MDD using proton magnetic resonance spectroscopy (1H-MRS).This community-based study used a cross-sectional design using 3-T 1H-MRS in participants not taking MDD medication recruited from the community. The sample consisted of 251 healthy controls, 98 participants with a history of past MDD, and 47 participants who met the diagnostic criteria for current MDD. Diagnostic groups were comparable regarding age, education, income, and diet. Data were collected from March 2014 to October 2021, and data were analyzed from October 2021 to June 2022.GABA, Glx, Glu, and Gln concentrations in the left dorsolateral prefrontal cortex.Of 396 included participants, 258 (65.2%) were female, and the mean (SD) age was 25.0 (4.7) years. Compared with healthy controls, those with past MDD and current MDD had lower GABA concentrations (mean [SEM] concentration: healthy controls, 2.70 [0.03] mmol/L; past MDD, 2.49 [0.05] mmol/L; current MDD, 2.54 [0.07] mmol/L; 92 with past MDD vs 236 healthy controls: r = 0.18; P = .002; 44 with current MDD vs 236 healthy controls: r = 0.13; P = .04). Compared with healthy controls, those with past MDD also had lower Glu concentrations (mean [SEM] concentration: healthy controls, 7.52 [0.06] mmol/L; past MDD, 7.23 [0.11] mmol/L; 93 with past MDD vs 234 healthy controls: r = 0.16; P = .01) and higher Gln concentrations (mean [SEM] concentration: healthy controls, 1.63 [0.04] mmol/L; past MDD, 1.84 [0.07] mmol/L; 66 with past MDD 153 healthy controls: r = 0.17; P = .04).In a large, mostly medication-free community sample, reduced prefrontal GABA concentrations were associated with past MDD, consistent with histopathologic studies reporting reduced glial cell and GABA cell density in the prefrontal cortex in individuals with depression. Patients with MDD also demonstrated increased Gln levels, indicative of increased synaptic Glu release, adding to previous evidence for the Glu hypothesis of MDD.
Monkeypox virus productively infects human induced pluripotent stem cell-derived astrocytes and neural progenitor cells
Authors: Thanathom Chailangkarn, Samaporn Teeravechyan, Khemphitcha Attasombat, Theeradej Thaweerattanasinp, Kitpong Sunchatawirul, Pawita Suwanwattana, Krit Pongpirul, Anan Jongkaewwattana
Journal: Journal of Infection (2022)
Applications of focused ultrasound-mediated blood-brain barrier opening
Authors: Catherine M. Gorick, Victoria R. Breza, Katherine M. Nowak, Vinton W.T. Cheng, Delaney G. Fisher, Anna C. Debski, Matthew R. Hoch, Zehra E.F. Demir, Nghi M. Tran, Mark R. Schwartz, Natasha D. Sheybani, Richard J. Price
Journal: Advanced Drug Delivery Reviews (2022)
Value of Bone Marrow and Spleen Cell Suspensions for Survival of Lethally Irradiated Dogs&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Robert D. Sullivan, Gisela Stecher, Stephen S. Sternberg
Journal: JNCI Journal of the National Cancer Institute (1959)

The protective effect of homologous spleen and homologous marrow and of autologous spleen and autologous marrow was studied in 85 mongrel dogs after their single exposure to lethal doses of total-body X radiation. In the autologous experiments the material was administered intravenously and intra-arterially immediately after irradiation, while in the homologous experiments the cell suspensions were given as late as 24 hours after irradiation. No protection was noted with these techniques at radiation dose levels of 600 r, 550 r, and 450 r. Survival was somewhat longer at 450 r than at 600 r for both treated and control groups. Within the treated groups, however, there was no appreciable difference in survival at these radiation dosage levels. The delayed administration of homologous marrow up to 24 hours after irradiation and the use of antibiotics and cortisone were likewise without significant protection. In most animals of all groups, there was depression of the white blood cell count to less than 1,000 cells per mm.3 by the 6th to 9th day, and at post-mortem examination, marrow and lymphoid aplasia were found. Significant protection was noted when autologous marrow was used at radiation dose levels of 400 r. White cell count depression was less severe for the treated than for the control group. Surviving dogs were killed and were found to have normal hematopoietic and lymphatic systems. It is concluded that viable homologous or autologous spleen and marrow cell suspensions failed to protect the mongrel dog against supralethal doses of total-body radiation, but autologous marrow afforded some benefit at marginally lethal dosage levels.
Early Nitrogenase Ancestors Encompassed Novel Active Site Diversity
Authors: Sarah L Schwartz, Amanda K Garcia, Betül Kaçar, Gregory P Fournier
Journal: Molecular Biology and Evolution (2022)

Abstract Ancestral sequence reconstruction (ASR) infers predicted ancestral states for sites within sequences and can constrain the functions and properties of ancestors of extant protein families. Here, we compare the likely sequences of inferred nitrogenase ancestors to extant nitrogenase sequence diversity. We show that the most-likely combinations of ancestral states for key substrate channel residues are not represented in extant sequence space, and rarely found within a more broadly defined physiochemical space—supporting that the earliest ancestors of extant nitrogenases likely had alternative substrate channel composition. These differences may indicate differing environmental selection pressures acting on nitrogenase substrate specificity in ancient environments. These results highlight ASR's potential as an in silico tool for developing hypotheses about ancestral enzyme functions, as well as improving hypothesis testing through more targeted in vitro and in vivo experiments.
Intradermal vaccination of HPV-16 E6 synthetic peptides conjugated to an optimized Toll-like receptor 2 ligand shows safety and potent T cell immunogenicity in patients with HPV-16 positive (pre-)malignant lesions
Authors: Frank M Speetjens, Marij J P Welters, Marije Slingerland, Mariette I E van Poelgeest, Peggy J de Vos van Steenwijk, Inge Roozen, Sanne Boekestijn, Nikki M Loof, Gijs G Zom, A Rob P M Valentijn, Willem-Jan Krebber, Nico J Meeuwenoord, Catharina A H Janssen, Cornelis J M Melief, Gijs A van der Marel, Dmitri V Filippov, Sjoerd H van der Burg, Hans Gelderblom, Ferry Ossendorp
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Amplivant is a molecularly optimized Toll-like receptor 2 ligand that can be covalently conjugated to tumor peptide antigens. In preclinical models, amplivant-adjuvanted synthetic long peptides (SLPs) strongly enhanced antigen presentation by dendritic cells, T cell priming and induction of effective antitumor responses. The current study is a first-in-human trial to investigate safety and immunogenicity of amplivant conjugated to human papillomavirus (HPV) 16-SLP. Methods A dose escalation phase I vaccination trial was performed in 25 patients treated for HPV16 positive (pre-)malignant lesions. Amplivant was conjugated to two SLPs derived from the two most immunodominant regions of the HPV16 E6 oncoprotein. The vaccine, containing a mix of these two conjugates in watery solution without any other formulation, was injected intradermally three times with a 3-week interval in four dose groups (1, 5, 20 or 50 µg per conjugated peptide). Safety data were collected during the study. Peptide-specific T cell immune responses were determined in blood samples taken before, during and after vaccination using complementary immunological assays. Results Toxicity after three amplivant-conjugated HPV16-SLP vaccinations was limited to grade 1 or 2, observed as predominantly mild skin inflammation at the vaccination site and sometimes mild flu-like symptoms. Adverse events varied from none in the lowest dose group to mild/moderate vaccine-related inflammation in all patients and flu-like symptoms in three out of seven patients in the highest dose group, after at least one injection. In the lowest dose group, vaccine-induced T cell responses were observed in the blood of three out of six vaccinated persons. In the highest dose group, all patients displayed a strong HPV16-specific T cell response after vaccination. These HPV16-specific T cell responses lasted until the end of the trial. Conclusions Amplivant-conjugated SLPs can safely be used as an intradermal therapeutic vaccine to induce robust HPV16-specific T cell immunity in patients previously treated for HPV16 positive (pre-) malignancies. Increased vaccine dose was associated with a higher number of mild adverse events and with stronger systemic T cell immunity. Trial registration numbers NCT02821494 and 2014-000658-12.
Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours
Authors: Jeffrey L. Schaal, Jayanta Bhattacharyya, Jeremy Brownstein, Kyle C. Strickland, Garrett Kelly, Soumen Saha, Joshua Milligan, Samagya Banskota, Xinghai Li, Wenge Liu, David G. Kirsch, Michael R. Zalutsky, Ashutosh Chilkoti
Journal: Nature Biomedical Engineering (2022)
TransDFL: Identification of Disordered Flexible Linkers in Proteins by Transfer Learning
Authors: Yihe Pang, Bin Liu
Journal: Genomics Proteomics & Bioinformatics (2022)

Disordered flexible linkers (DFLs) are the functional disordered regions in proteins, which are the sub-regions of intrinsically disordered regions (IDRs) and play important roles in connecting domains and maintaining inter-domain interactions. Trained with the limited available DFLs, the existing DFL predictors based on the machine learning techniques tend to predict the ordered residues as DFLs, leading to a high falsepositive rate (FPR) and low prediction accuracy. Previous studies have shown that DFLs are extremely flexible disordered regions, which are usually predicted as disordered residues with high confidence [P(D) > 0.9] by an IDR predictor. Therefore, transferring an IDR predictor to an accurate DFL predictor is of great significance for understanding the functions of IDRs. In this study, we proposed a new predictor called TransDFL for identifying DFLs by transferring the RFPR-IDP predictor for IDR identification to the DFL prediction. The RFPR-IDP was pre-trained with IDR sequences to learn the general features between IDRs and DFLs, which is helpful to reduce the false positives in the ordered regions. RFPR-IDP was fine-tuned with the DFL sequences to capture the specific features of DFLs so as to be transferred into the TransDFL. Experimental results of two application scenarios (prediction of DFLs only in IDRs or prediction of DFLs in entire proteins) showed that TransDFL consistently outperformed other existing DFL predictors with higher accuracy. The corresponding web server of TransDFL can be freely accessed at http://bliulab.net/TransDFL/.
Genome-wide CRISPR screens identify combinations of candidate latency reversing agents for targeting the latent HIV-1 reservoir
Authors: Weiwei Dai, Fengting Wu, Natalie McMyn, Bicna Song, Victoria E. Walker-Sperling, Joseph Varriale, Hao Zhang, Dan H. Barouch, Janet D. Siliciano, Wei Li, Robert F. Siliciano
Journal: Science Translational Medicine (2022)

Reversing HIV-1 latency promotes killing of infected cells and is essential for cure strategies; however, no single latency reversing agent (LRA) or LRA combination have been shown to reduce HIV-1 latent reservoir size in persons living with HIV-1 (PLWH). Here, we describe an approach to systematically identify LRA combinations to reactivate latent HIV-1 using genome-wide CRISPR screens. Screens on cells treated with suboptimal concentrations of an LRA can identify host genes whose knockout enhances viral gene expression. Therefore, inhibitors of these genes should synergize with the LRA. We tested this approach using AZD5582, an activator of the noncanonical nuclear factor κB (ncNF-κB) pathway, as an LRA and identified histone deacetylase 2 (HDAC2) and bromodomain-containing protein 2 (BRD2), part of the bromodomain and extra-terminal motif (BET) protein family targeted by BET inhibitors, as potential targets. Using CD4+ T cells from PLWH, we confirmed synergy between AZD5582 and several HDAC inhibitors and between AZD5582 and the BET inhibitor, JQ1. A reciprocal screen using suboptimal concentrations of an HDAC inhibitor as an LRA identified BRD2 and ncNF-κB regulators, especially BIRC2, as synergistic candidates for use in combination with HDAC inhibition. Moreover, we identified and validated additional synergistic drug candidates in latency cell line cells and primary lymphocytes isolated from PLWH. Specifically, the knockout of genes encoding CYLD or YPEL5 displayed synergy with existing LRAs in inducing HIV mRNAs. Our study provides insights into the roles of host factors in HIV-1 reactivation and validates a system for identifying drug combinations for HIV-1 latency reversal.
The clinical and molecular characteristics of progressive hypothalamic/optic pathway pilocytic astrocytoma
Authors: Xiaoyu Li, Daniel C Moreira, Asim K Bag, Ibrahim Qaddoumi, Sahaja Acharya, Jason Chiang
Journal: Neuro-Oncology (2022)

Abstract Background Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) often progresses despite multiple therapies. Identifying clinical and molecular characteristics of progressive tumors may aid in prognostication and treatment. Methods We collected 72 unresectable, non-neurofibromatosis type 1-associated hypothalamic/optic pathway PA to identify clinical and biologic factors associated with tumor progression. Tumors that progressed after therapy, metastasized, or resulted in death were categorized into Cohort B; those that did not meet these criteria were categorized into Cohort A. DNA methylation and transcriptome analyses were performed on treatment-naïve tumors, and the findings were validated by immunohistochemistry (IHC). Results The median follow-up of the entire cohort was 12.3 years. Cohort B was associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs 6.7 years, P = .005), and high incidence of KIAA1549-BRAF fusion (81.5% vs 38.5%, P = .0032). Cohort B demonstrated decreased CpG methylation and increased RNA expression in mitochondrial genes and genes downstream of E2F and NKX2.3. Transcriptome analysis identified transcription factor TBX3 and protein kinase PIM1 as common downstream targets of E2F and NKX2.3. IHC confirmed increased expression of TBX3 and PIM1 in Cohort B tumors. Gene enrichment analysis identified enrichment of MYC targets and MAPK, PI3K/AKT/mTOR, and p53 pathways, as well as pathways related to mitochondrial function. Conclusions We identified risk factors associated with progressive PA. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognostication.
Predictors of impaired antibody response after <scp>SARS‐CoV</scp>‐2 <scp>mRNA</scp> vaccination in hematopoietic cell transplant recipients: A Japanese multicenter observational study
Authors: Yasuo Mori, Naoyuki Uchida, Takuya Harada, Yuta Katayama, Atsushi Wake, Hiromi Iwasaki, Tetsuya Eto, Satoshi Morishige, Tomoaki Fujisaki, Yoshikiyo Ito, Tomohiko Kamimura, Tsutomu Takahashi, Yutaka Imamura, Kazushi Tanimoto, Kenji Ishitsuka, Junichi Sugita, Noriaki Kawano, Kazuki Tanimoto, Goichi Yoshimoto, Ilseung Choi, Tomonori Hidaka, Ryosuke Ogawa, Yasushi Takamatsu, Toshihiro Miyamoto, Koichi Akashi, Koji Nagafuji
Journal: American Journal of Hematology (2022)

HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/μL, 1 points), absolute B-cell counts (<100/μL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.